ATP13A2 and Susceptibility to Neurodegeneration

项目概要/摘要 与糖尿病相关的神经退行性疾病对数百万人的健康和经济构成越来越大的威胁 每年.遗传易感性、环境暴露和年龄都会增加患上糖尿病的风险。 神经退行性疾病，如突触核蛋白病和锰中毒。ATP酶ATP 13 A2是 与多种年龄相关的神经退行性疾病相关，包括帕金森病， 常见的突触核蛋白病，神经元蜡样脂褐质沉着症，锰中毒，可能是一个重要的 与神经退行性疾病的关键风险因素相关的蛋白质。基因-环境相互作用的鉴定 与神经退行性疾病相关的疾病是早期发现、预防和治疗的重要一步。的 本研究的目的是确定ATP 13 A2是如何参与线粒体的维持，以及它是如何影响线粒体的功能的。 与环境和遗传风险因素相互作用，导致神经变性。它是假设 ATP 13 A2功能的丧失使神经元更容易受到锰和α-突触核蛋白毒性的影响 通过参与线粒体维护的机制，包括修复和清除机制。 此外，这种破坏可能与衰老和蛋白质积累相互作用，以产生增强的免疫应答。 神经变性和行为功能障碍。我们最近的数据表明，在糖尿病患者中，ATP 13 A2的功能丧失， 小鼠对锰的反应增强，大脑病理学也增加。指导 这一假设将通过追求三个具体目标进行测试：1）确定 ATP 13 A2功能的丧失对体内线粒体维持的影响，2）评估ATP 13 A2的神经毒性后果。 在存在ATP 13 A2的情况下Mn暴露对脑和外周线粒体功能的影响，以及3） 确定ATP 13 A2功能丧失和α-突触核蛋白负荷增加对线粒体 维持和体内生物能量学。这些研究的结果预计将产生积极的影响 基于我们对基因-环境相互作用如何导致细胞功能障碍的理解， 神经退化和行为障碍。

Project Summary/Abstract Age-related neurodegenerative diseases are an increasing health and economic threat for millions of people each year. Genetic susceptibility, environmental exposures, and age can all increase the risk of developing neurodegenerative conditions such as synucleinopathies and manganism. The ATPase ATP13A2 is associated with multiple age-related neurodegenerative conditions including Parkinson’s disease, the most common synucleinopathy, Neuronal Ceroid Lipofuscinosis, and manganism and may be an important protein linking key neurodegenerative disease risk factors. Identification of gene-environment interactions associated with neurodegeneration is an important step to early detection, prevention, and treatment. The objective of this proposal is to determine how ATP13A2 is involved in mitochondrial maintenance and how it interacts with environmental and genetic risk factors to cause neurodegeneration. It is hypothesized that loss of ATP13A2 function makes neurons more vulnerable to manganese and alpha-synuclein toxicity through mechanisms involved in mitochondrial maintenance including repair and clearance mechanisms. Further, this disruption may interact with aging and protein accumulation to produce enhanced neurodegeneration and behavioural dysfunction. Our recent data shows that loss of function of ATP13A2 in mice leads to an enhanced response to manganese and increased pathology in the brain. Guided by preliminary data this hypothesis will be tested by pursuing three specific aims: 1) Determine the impact of loss of ATP13A2 function on mitochondrial maintenance in vivo, 2) Assess the neurotoxic consequences of Mn exposure in the presence of ATP13A2 loss on mitochondrial function in brain and periphery, and 3) Identify the impact of loss of ATP13A2 function and increased alpha-synuclein burden on mitochondrial maintenance and bioenergetics in vivo. Results from these studies are expected to have a positive impact on our understanding of how gene-environment interactions can contribute to cellular dysfunction, neurodegeneration, and behavioral impairments.